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Impairment of the glutamatergic system is also crucial for neuronal survival, as it can cause synaptic dysfunction that overstimulates glutamate receptors, especially N-methyl-d-aspartate receptors (NMDARs). Another protein affecting neuronal health is glycogen synthase kinase-3 (GSK3), a widely preserved serine\/threonine protein kinase linked to neuronal disorders, including AD. In recent years, alkaloids from the Amaryllidaceae have received great attention for their known anticholinergic activity, as well as their antioxidant, antigenotoxic, and neuroprotective properties. In this context, the identification of compounds capable of interacting with different targets involved in AD provides a possible new therapeutic strategy. In this study, we conducted a combination of in vitro and in silico approaches to identify the potential of <jats:italic>C. subedentata<\/jats:italic> in regulating key proteins involved in AD. Viability and neuroprotection assays were performed to evaluate the neuroprotection exerted by <jats:italic>C. subedentata<\/jats:italic> extract against neurotoxicity induced by A\u03b2 (1\u201342) peptide and Okadaic acid in SH-SY5Y cells. Computational methods such as docking and molecular dynamic and viability therapeutic analysis were conducted to explore the interaction of alkaloids from <jats:italic>C. subedentata<\/jats:italic> with target proteins (AChE, BuChE, NMDA, and GSK-3) involved in AD. Our findings show that C. <jats:italic>subedentata<\/jats:italic> extract exerts neuroprotective effects against neurotoxic stimuli induced by A\u03b2 (1\u201342) peptide and Okadaic acid. In addition, in silico approaches provide insight into how <jats:italic>C. subedentata<\/jats:italic> extract alkaloids interact with key proteins involved in AD. These findings provide insights into the potential therapeutic effects and action mechanisms of these alkaloids. We hope these rapid findings can contribute as a bridge to the identification of new molecules with the potential to counteract the effects of AD.<\/jats:p>","DOI":"10.1007\/s11064-025-04354-6","type":"journal-article","created":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T05:01:44Z","timestamp":1741410104000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Alkaloids from Caliphruria subedentata (Amaryllidaceae) as Regulators of AChE, BuChE, NMDA and GSK3 Activity: An In Vitro and In Silico Approach for Mimicking Alzheimer\u00b4s Disease"],"prefix":"10.1007","volume":"50","author":[{"given":"Willian Orlando Castillo","family":"Ordo\u00f1ez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilza Velasco","family":"Palomino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia Eugenia V\u00e9lez","family":"Varela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivon Bola\u00f1os","family":"Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levy Bueno","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvana","family":"Giuliatti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,8]]},"reference":[{"key":"4354_CR1","unstructured":"Prince MJ (2015) World Alzheimer Report 2015: the global impact of dementia: an analysis of prevalence, incidence, cost and trends. 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